Members of the neurogenic basic-Helix-Loop-Helix (bHLH) gene family are expressed at different periods o neuronal determination and differentiation. The broad hypothesis of this application is that specific physical properties of each neurogenic bHLH protein confer a distinct function during neuronal development. The long term goal is to understand the molecular mechanism of generating specific neuronal phenotypes. The work proposed in this application will identify the special role of neuroD2 in neuronal differentiation and the physical mechanism of fulfilling that role. The specific aims will: (i) identify the mechanism of regulating the activity of the neuroD2 transcription factor; (ii) determine whether regulation of the activation domain or regulation of DNA binding controls neurogenesis by neuroD2; and (iii) identify the role of neuroD2 in Purkinjie cell differentiation. The significance is that understanding the molecular basis of neuronal diversity will provide the foundation for the rational manipulation of cell phenotype for the treatment of human disease. Th health relatedness of this work is that the ability to generate neurons and neuroendocrine cells will be critical for the treatment of numerous human diseases.